Quick consults in hematology: Staging and treating immunoglobulin light chain (<scp>AL</scp>) amyloidosis
Authors: Morie Gertz
Journal: American Journal of Hematology (2023)

A 67-year-old man was found to have proteinuria on a Medicare annual physical. He is referred to a nephrologist who performed a kidney biopsy showing amyloidosis confirmed to be immunoglobulin light chain by mass spectroscopic analysis. The patient is referred to you for further management. What is the appropriate diagnostic management for this patient: This patient needs a thorough evaluation to determine the extent of the amyloid which may be present outside of the kidney. Eighty-three percent of patients that present with renal amyloid nephrotic syndrome will have amyloid deposits outside of the kidney.1 Diagnostic evaluation should include the heart with echocardiography to include Doppler studies and global longitudinal strain. Cardiac biomarkers NT-proBNP and troponin provide insights as to the extent of cardiac cellular damage and cardiac insufficiency, these biomarkers also form the basis for the staging of amyloidosis. For most patients' cardiac magnetic resonance imaging is not required in the presence of a good quality echocardiogram. Alkaline phosphatase is the best laboratory measure for hepatic involvement. Right-sided heart failure may influence liver function, but this tends to impact transaminase levels making alkaline phosphatase a rather specific measure for liver involvement. Proof that there is an underlying clonal plasma cell dyscrasia is required before initiating anti plasma cell chemotherapy and should include immunofixation of serum and 24-h urine as well as immunoglobulin free light chain assay. A bone marrow should be performed when AL amyloidosis is confirmed by mass spectroscopic analysis of tissues. This allows the exclusion of overt multiple myeloma which may be an important consideration when the question of maintenance therapy comes up. In addition half of patients with light chain amyloidosis have the t(11;14) translocation. This is an important finding because if second-line therapy is required venetoclax may be an effective option in the presence of this translocation. In some instances, the diagnosis of amyloidosis can be verified non-invasively because 50% of bone marrow biopsies in amyloidosis patients will be Congo red positive. Exclusion of peripheral nerve amyloid can often be effectively performed using history and physical examination and does not routinely require electromyography. First-line therapy: (Figure 1) The ANDROMEDA trial was a randomized, open label, active controlled phase 3 study of daratumumab, bortezomib, cyclophosphamide, dexamethasone versus bortezomib, cyclophosphamide, and dexamethasone alone in treatment naive patients with immunoglobulin light chain amyloidosis. The key eligibility criteria required amyloid involvement of one organ and specifically excluded patients with an estimated glomerular filtration rate less than 20 mL/min. Patients also had to have an NT proBNP less than 8500 pg/mL. Patients in the control arm received standard weekly bortezomib, weekly cyclophosphamide, and weekly dexamethasone for a total of 24 weeks. In the daratumumab arm patients received the same dosing of bortezomib, cyclophosphamide, and dexamethasone but also received daratumumab 1800 mg subcutaneously weekly for 8 weeks, every other week for 16 weeks, and then every 4 weeks for an additional 80 weeks. The primary endpoint of the study was overall hematologic complete response. At a median follow-up of 11.4 months the daratumumab group had a hematologic complete response rate of 53.3% compared to the control arm 18.1%.2 Hematologic response is important but only in so far as it leads to an organ response. Treating AL amyloidosis has several Goals: One is the prevention of end-stage renal or cardiac failure, another is preventing deposition of amyloid in other organs such as lung, nerve, and liver. Organ response results in prevention of end stage renal disease and advanced cardiac failure producing improved survival and improved quality of life. Hematologic response without organ response does not represent successful therapy. In the ANDROMEDA trial at 6 months the daratumumab containing arm showed a renal response of 53% compared to 23.9% in the non-daratumumab arm. Cardiac responses were seen in 41.5% of the daratumumab group versus 22.2% in the control group. In some patients advanced end organ damage is beyond recovery emphasizing the need for early diagnosis. In a follow-up trial daratumumab was administered to patient's ineligible for ANDROMEDA by virtue of advanced cardiac failure defined as an NT proBNP greater than 8500 pg/mL. Despite advanced cardiac disease the 12-month overall survival rate was 47% overall hematologic response was 74%.3 This suggests a trial of therapy is indicated for virtually all patients. What are the key monitoring end points of my treatment: Unlike multiple myeloma where patients with indolent disease may do well long-term with a partial response, this does not apply to amyloidosis. It is also important to note that the hematologic response criteria for amyloidosis differ from the hematologic response criteria for multiple myeloma. Patients that have a partial response defined by a 50% reduction in the dFLC have much shorter survival and a lower organ response rate than patients who achieve a very good partial response or better.4 Therefore, patients who failed to achieve a very good partial response after 4 cycles of therapy need to be considered for second-line therapy even in the face of a significant light chain reduction. Unfortunately, there are patients that achieve a hematologic response but still do not evidence an organ response. There is no consensus as to when second-line intervention should be introduced. A recent consensus review outlines the use of salvage stem cell transplantation for patients failing to achieve an adequate response.5 Models have been developed that integrate multiple organ and hematologic responses to predict early clinical benefit and may provide an early signal for the need to change therapy.6 What are my options for patients who either failed to achieve a very good partial response with first-line therapy or have a deep response but subsequently relapse and require salvage therapy? As many as 40% of patients will fail to achieve a deep hematologic response with first-line chemotherapy making a subsequent organ response quite unlikely. In addition, despite the indolent nature of the plasma cells in AL amyloidosis recurrence is common and there can be a need for second-line therapy for light chain amyloidosis patients. If the patient had not previously been exposed to daratumumab this would be important in a second-line combination. Stem cell transplantation is a highly effective intervention for AL amyloidosis. Its utilization has fallen significantly with the introduction of daratumumab based therapy. However, the kinetics of myeloablative doses of melphalan are significant even in patients that have previously received oral weekly cyclophosphamide. The use of stem cell transplantation as consolidation to try and deepen the response to induction therapy is done in a manner very similar to that of multiple myeloma. Special precautions are required for patients with amyloidosis reducing the pool of eligible patients for this technique. European myeloma network guidelines for safe transplantation have included age under 70, left ventricular ejection fraction greater than or equal to 40%, systolic blood pressure greater than 90, NT proBNP less than 5000 pg/mL and a high sensitivity troponin T less than 75 ng/mL. Patients with significant proteinuria should have a serum creatinine less than 2 mg/dL.7 For patients that are too high risk for myeloablative chemotherapy, venetoclax should be considered for those patients that demonstrate t(11;14). In a case series of 12 patients with relapsed disease venetoclax produced a complete response in 4 and a very good partial response in an additional 3 patients, overall response 58%.8 In a European case series, the hematologic complete response rate was 78% used in both relapsed patients and as consolidation. Venetoclax produced a hematologic response rate of 81% when t(11;14) was identified.9 It can be used in combination with Daratumumab, dexamethasone or bortezomib.10 It has not been demonstrated that combinations of venetoclax excepting dexamethasone offer an advantage. Immunomodulatory agents particularly lenalidomide but including pomalidomide can significantly exacerbate cardiac symptoms in patients with any degree of cardiac amyloidosis. This has led to their use only in 2nd or 3rd line. When combined with dexamethasone in a dose of 20 mg very good partial response or better has been reported in 18%–37% of patients. Toxicities associated with this regimen in the amyloid population included myelosuppression in 26%–45%, renal failure in 3%–7.5%, cardiac arrhythmias in 0%–21% and a rise in NT proBNP in the majority.11 Given the high activity of bortezomib in the treatment of light chain amyloidosis it would not be surprising to find that both ixazomib and carfilzomib are active. In a phase 3 trial of ixazomib and dexamethasone versus physician's choice, ixazomib had a favorable hazard ratio of 0.5 with a median time to vital organ deterioration or death of 34.8 months compared to 26.1 months.12 Carfilzomib has also been used but its administration in AL amyloidosis is challenging with 36% showing cardiac toxicity and a maximum tolerated dose of 36 mg/m2. The very good partial response rate or better with carfilzomib was 39%.13 Bendamustine has been used in the management of AL amyloidosis in the refractory relapsed setting. In a trial of 31 patients receiving 4–6 cycles 11% achieved a complete response and in 18% a very good partial response. An overall organ response rate was seen of 29%. No therapy related deaths were seen. The most common toxicity was hematologic, and the median progression-free survival was 11.3 months.14 Although it has been withdrawn from the market, belantamab has produced an overall response rate of 64% and a very good partial response or better of 55%.15 IgM amyloidosis represents 7% of all patients with light chain amyloidosis. The responsible cell for light chain production is a lymphoplasmacytic cell usually demonstrating MYD88 mutation rather than the CD 38+ plasma cell of the more common forms of light chain amyloidosis. Therapies have been developed from active regimens in macroglobulinemia.16 Conclusion: Highly effective therapy is now available for AL amyloidosis, but a good outcome requires an early diagnosis before the development of dialysis dependent renal failure or end-stage cardiomyopathy. When the diagnosis is made late in the disease course even the most highly effective anti-plasma cell chemotherapy cannot produce reversal of organ failure. Hematologists need a high index of suspicion when monitoring patients with monoclonal gammopathy of undetermined significance or smoldering multiple myeloma. Screening of smoldering multiple myeloma patients over time using cardiac biomarkers and monitoring for albuminuria will increase recognition of this devastating disease early. Dr. Gertz reports personal fees from Ionis/Akcea, honorariaum from Alnylym, personal fees from Prothena, personal fees from Sanofi, personal fees from Janssen, personal fees from Aptitude Healthgrants and personal fees from Ashfield Meetings personal fees from Juno, personal fees from Physicians Education Resource, personal fees for Data Safety Monitoring board from Abbvie, fees from Johnson & Johnson, and Celgene, personal fees from Research to Practice, Meetings personal fees from Sorrento, Development of educational materials for i3Health. Data sharing not applicable—No new data generated.